Hexadecahydro-17-(8-hydroxyl-alpha-methylbutyl)-10, 13-dimethyl-15h-cyclopenta[a]phenanthrene-3, 7, 12-trione and derivatives thereof



United States Patent 2,758,992 Patented Aug. 14, 1956 fine No Drawing. Application March 14, 1955, Serial No. 494,234

6 Claims. (CL 260-23955) This invention relates to hexadecahydro-17-(6-hydroxya methylbutyl) 10,13 dimethyl H cyclopenta- [a]phenanthrene-2,7 l2 trione, its esters and cyclic ketals, and -to .processes for the manufacture thereof.

More particularly, this invention relates to compounds of the formula wherein R 'is either hydrogen or a lower alkanoylradical; and Z, Z' and 'Z" are each carbonyl radicals or 1,3-bxathiolane radicals of the formula in which the carbon atom at position 2 is a so-called spiro atom, being uniquely common to both the oxathiolane and (one of the.) cyclopentahlphenanthrene rings. By lower alkanoyl is meant wherein Alk is defined as an alkyl group containing fewer than 7 carbon atoms.

The compounds of this invention possess valuable pharmacological properties. Especially, the compounds are useful because of their regulatory eifect on the cardiovascular system. For example, they are of particular importance as anti-hypertensive agents. Moreover, the compounds disclosed herein manifest a myotrophic activity uncomplicated by the capacity for testoid stimulation which characterizes the naturally occurring substances known to increase muscle strength and mass. Still further, the claimed compounds possess a desirable choleretic action. Distinct from cholagogs, which merely promote the expulsion of stored bile from the gall bladder, the subject materials have the property of augmenting the volume output of bile from the liver.

The compound of this discovery are relatively insoluble in water but may be dissolved in alcohol, dioxane, and other common organic solvents. The compounds may be administered in solid form as tablets or capsules; dissolved or suspended in aqueous media, they may be given parenterally.

The compounds to which this invention relates may be prepared from a suitable oxygenated cyclope'ntalalphensubject anthrene-by way of example, dehydrocholic acidas follows: Dehydrochol-ic acid is reacted with p-mercaptoethanol in the presence of an acidic condensing agent such as zinc chloride or p toluenesulfonic acid to produce, upon saponification of the primary product, the corresponding cyclic ketal (3,7,1 2). This material is converted to a simple ester, as with diazomethane, which ester, in turn, is reduced with lithium aluminum hydride or the equivalent to give the u-hydroxy derivative. It is then possible to efiect selective hydrolysis of the three cyclic ketal groups present in the molecule so as to afford the mono-, di-, and triketo alcohols corresponding. Thus, treatment with (in effect) 'very dilute alcoholic hydrogen chloride yields the 3-oxo-17,12-ketal, while sulfuric acid in aqueous di'oXa'ne gives a separable mixture or the lldioXo-lZ-ketal and the trione. An alternative, ofttimes preferable route to the aforesaid trione proceeds from the 3,7,l'2-ketal by heating with acetic acid containing a small amount of hydrochloric acid and saponifying the triketo-B-ester which results. Other u-es'ters of the tr'io'n'e in question are obtained by contacting the parent alcohol with an acid anhydride of choice in the presence of a basic catalyst such as pyridine. These esters, in turn, may be converted to corresponding ketals withfl-mercapto-ethanol as above.

Inasmuch as the reactivities of the keto groups of dehydrocholic acid are known to decrease in the order 3 7 l2, particular structures assigned the hereinaft r claimed ketals are highl robable albeit not roved. For present pur oses, however, structural ambiguities would he nowise detrimental, since the burden of the present disclosure is compounds useful by reason of the physiological properties iuheriug therein, regardless of structure, and means whereby they may be prepared.

The following exam les will illustrate in detail certain of the compounds which constitute the resent invention and methods which have been devised for their preparation. However, the invention is not to be construed as limited thereby, either in spi'rit or in scope, since it will be apparent to those kill d in the art of organic synthesis that many modifications, both of materials and of methods, ma be practiced Without departin from the pur ose and intent of this disclosure. In the examples hereinafter detailed, tem eratures are given in degrees Centigrade C.) and relative amounts of materials in parts by Weight, except as otherwise noted. Specific rotations refer to the D line of sodium and were determined in dioxane solution at room temperature.

EXAMPLE 1 Hexadecahydro 17 ('y carboxy oz methylpr0pyl)- 10,13 dimethyl trz'spz'roUSH cyclopenta[a]phenanthrene 3,2 (1',3)0xathi0lane 7,2" (1",3") oxathiolane-12,2"'-(1",3")0xathi0lane] A mixture of 82 parts of dehydrocholic acid, 88 parts of B-mercaptoethanol, and 1 part of p-toluenesulfonic acidmonohydrate in 1565 parts of toluene is heated at reflux temperatures for 18 hours, water being removed as formed in process. Toluene is then distilled oft and the residue dissolved in 725 parts of 90% (v./v.) aqueous methanol containing 80 partsof potassium hydroxide. The solution is heated at reflux temperatures for 2 hours, following which it is poured into an excess of cold dilute muriatic acid. The product is extracted with benzene. Concentration of the benzene extract and subsequent dilution with methanol effects, on cooling, precipitation of the desired cyclic ketal. A second crop of product is obtained by dilution of the mother liquor with additional methanol. Recrystallization of the material thus obtained from a mixture of benzene and methanol gives long needles which sinter in the'neighborhood of C. and melt 3 at approximately 155 C. The product shows a specific rotation of +92". It has the formula HGOH= CH3 (BEF-GHnOHaCOOH CH: CH:

EXAMPLEZ ester, sintering at 177 C. and melting at approximately 183 C. The product has a specific rotation of +90.

EXAMPLE 3 Hexadecahydro 17 (6 hydroxy a. methylbutyl)- 10,13 dimethyl trispiro [15H cyclopentflalphenanthrene 3,2 (1,3')0xathz'olane 7,2" (1",3") oxathilane-12,2"'-(1",3)oxathiolane] .A solution of 155 parts of the ester of the foregoing Example 2 in 3500 parts of anhydrous ether is added very slowly with agitation to a suspension of 19 parts of lithium aluminum hydride in 1400 parts of anhydrous ether. The resultant mixture is heated at reflux temperatures for 2 hours and then allowed to stand overnight. To the mixture is cautiously added with agitation 1000 parts of approximately aqueous sulfuric acid. The ether layer is separated, dried over anhydrous sodium sulfate, and stripped of solvent by'distillation, leaving a residue which, twice recrystallized from a mixture of benzene and methanol, appears as needles, M. P. 233-235 C., specific rotation +95 The desired product thus obtainedhas the formula flomcmomon CH: CH;

0 /s H1O CH1 EXAMPLE4 Hexadecahydro 17 (6 hydroxy u methylbutyl) 10,13 dimethyl dispir0[15H cyclopentaEalphenanthrene 7,2 (1',3')0xathi0lane 12,2" (1",3") oxathiolane] 3 0ne.A solution of 20 parts of the alcohol of the preceding Example 3 in 1200 parts of anhydrous methanol containing 33 parts of acetyl chloride is heated at reflux temperatures for 5 hours. Methanol is then distilled ofi and the residue taken up in ether. The ether solution is washed with aqeuous sodium bicarbonate, dried over anhydrous sodium sulfate, and chromatographed on silica, using ethyl acetate and ben- I crystallized from a mixture of benzene and cyclohexane,

shows M. P. approximately 212214 C. and a specific rotation of +43. The desired material is thus obtained as thick needles and has the formula Hie- 011,

. HCHICHiCHflOH CH3 CH3 V CH:

EXAMPLE 5 A. H exadecahyd r0-] 7 fi-hydroxy -a-methy lb utyl -1 0,- 13 dimethyl 15H cyclopenta[alphenanihrene 3,7,12- tri0ne.-A solution of 7 parts of the alcohol of Example 3 in 315 parts of dioxane containing 35 parts of water and 15 parts of concentrated sulfuric acid is heated at reflux temperatures for 22 hours, then neutralized with solid sodium bicarbonate and, finally, filtered. The filtrate is stripped of solvent by vacuum distillation and the resi due taken up in methanol. A crystalline precipitate (crop 1) comes down on standing. The precipitate is filtered off for subsequent purification and the mother liquor then evaporated to dryness. The residue is taken up in 13 parts of benzene and this solution diluted with 5 volumes of ether. A crystalline precipitate (crop 2) forms in process. This precipitate is filtered 013?, combined with crop 1, and the material thus accumulated crystallized from methanol. There results hexadecahydro-17-(a-hydroxy-u-methylbutyl)-10,l3 dimethyl 15H- cyclopenta[a]phenanthrene,3,7,12-trione, M. P. 212-2l3 C., specific rotation +28", the formula of which is HCHaCHaGHzOH CH3 B. Hexadecahydro-I7-(6-hydroxy-m-methylbutyl) 10,- 13-dimethyl-spiro[15H-cyclopentaEa] phenanthrene-12,2'- (1,3')oxathiolane]-3,7-di0ne.The mother liquor from crop 2 in the preceding Part A of this example is evaporated to dryness and the residue washed by trituration with ether. Washings are discarded and the dried residue twice crystallized from methanol. By this means there is obtained the desired monoketal, M. P. 182-183 C., specific rotation +57.5. The product has the formula HgC-CH:

' HCHsCHzCHaOH CH3 CH3 k5 EXAMPLE 6 hydroxy-a-methylbuPYDiI 0,,1 3-iiimethyl 415E oyclopenta [a]phenanthrene-3;7,T2 trionein 10 parts of pyridine and 6 parts of acetic anhydride is allowed to stand overnight at room temperatures. The solution is then diluted with a 1:1 (by volume) mixture of ether and benzene, and the diluted solution washed in turn with aqueous acid, aqueous alkali, and water, following which it is dried over anhydrous sodium sulfate and, finally, concentrated by distillation to a relatively small volume. Upon addition of anhydrous ether, the desired aoetoxyl compound crystallizes as fine needles, M. P. approximately 203-204 C. Specific rotation is +26". The product has the formula B. To a solution of 2 parts of the ketal alcohol of the hereinabove detailed Example 3 in 50 parts of glacial acetic acid is added 1 part of concentrated muriatic acid, following which the reactants are heated at reflux temperatures for 22 hours. Acetic acid is removed by vacuum distillation and the residue washed by trituration with ether. The dried residue, crystallized from a mixture of benzene and normal hexane, gives fine needles of hexadecahydro- 17-(fi-acetoxy-a-methylbutyl)-10,13-dimethyl-15H cyclopenta[a]phenanthrene,3,7,12-trione identical with the product obtained in Part A preceding.

EXAMPLE 7 Hexadecahydro-1 7-( fi-valeryloxy-a-mcthylbutyl -1 0,13- dimethyl H cyclopenta[alphenamhrene 3,7,12 tri- 0ne.By substituting 11 parts of valeric anhydride for the 6 parts of acetic anhydride used in the procedure of Example 6A above, hexadecahydro-17-(6-valeryloxy-a-methylbutyl) 10-13-dimethyl-1SH-cyclopenta[alphenanthrene-3,- 7,12-trione is obtained. The product has the formula What is claimed is: 1. A compound having the formula wherein R {is selected from the group A consisting of in which the carbon atom at position 2 is a spiro atom uniquely common to both the oxathiolane and cyclopenta[a]phenanthrene rings.

2. Hexadecahydro 17 (6 hydroxy a methylbutyl) 10,13 dimethyl trispiro[15H cyclopenta[a]- phenanthrene 3,2 (1',3')oxathiolane 7,2" (1",3") oxathiolane-l2,2'-(1",3"')oxathiolane].

3. Hexadecahydro 17 (5 hydroxy a methylbuty-l) 10,13 dimethyl 15H cyclopenta[alphenanthrene-3,7, 12-trione.

4. Hexadecahydro 17 (6 acetoxy 0: methylbutyl) 10,13 dimethyl 15H cyclopenta[a]phenanthrene-3,7,12-trione. I

5. In a process for preparing compounds of the formula wherein R is selected from the group consisting of hydrogen and lower alkanoyl radicals; and Z, Z, and Z" are selected from the group consisting of carbonyl radicals and 1,3-oxathiolane radicals having the formula in which the carbon atom at position 2 is a spiro atom uniquely common to both the oxathiolane and cyclopenta[a]phenanthrene rings, the step which comprises contacting hexadecahydro 17 ('y alkoxycarbonylu methylpropyl) 10,13 dimethyl trispiro[15H- cyclopenta[a]phenanthrene 3,2 (1',3')oxathio1ane- 7,2 (1",3")oxathiolane 12,2' (1',3)oxathiolane] with lithium aluminum hydride.

6. In a process for preparing compounds of the formula are selected from the group consisting of carbonyl radileak and '1 3-oxathio1ane radicals having the formula in which the carbon atom at position 2 is a spiro atom uniquely common to both the oxathiolane and cyc1openta-[a1phenanthrene rings, the step which comprises contacting hexadecahydro 17 ('y methoxycarbonyL 'a methylpropyl) 10,13 dimethyl trispiro[15H- No. references cited. 

1. A COMPOUND HAVING THE FORMULA WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND LOWER ALKANOYL RADICALS; AND Z, Z'', AND Z" ARE SELECTED FROM THE GROUP CONSISTING OF CARBONYL RADICALS AND 1,3-OXATHIOLANE RADICALS HAVING THE FORMULA 